Lactams are compounds of high interest due to their biological activities, for example well known β-lactams such as some penicillins, cephalosporins and carbapenems have antibacterial activity.
Spirolactams are one particular class of lactams that have shown interesting biological properties. Some spiro-fused azetidinones have been described as having antibacterial activity, see U.S. Pat. No. 4,680,388, or hypocholesterolemic properties, see for example WO 94 17038. Additionally, if these compounds have the adequate functionality they are valuable intermediates towards different families of compounds. The spirolactam ring is the equivalent of an alpha amino or hydroxy aminoacid and opens many possibilities in diastero and/or enantioselective synthesis.
There are few synthetic processes available for this class of compounds. WO 96 27587 describes the catalytic enantioselective synthesis of certain spirolactams that involves a large number of steps. U.S. Pat. No. 5,734,061 also describes a process for the preparation of spirocyclic lactams N-substituted with a tertiary amine susbtituent. U.S. Pat. No. 4,680,388 describes procedures to obtain N-sulphate substituted spirolactams. These processes and the intermediates used in them are directed to very particular compounds and therefore lack a wider applicability due to the absence of reactive functional groups.
Miyazawa, E. et al. in Heterocycles, vol 59, 1:149-160 “Synthesis of spiro-fused nitrogen heterocyclic compounds via N-methoxy-N-acylnitrenium ions using phenyliodine (III) bis(trifluoroacetate) in trifluoroethanol” describe another process to obtain functionalised spirolactams including some spirodienones.
Glover, S. A. et al. in Tetrahedron, 1987, 43:2577-2592 “N-alkoxy-N-acylnitrenium ions in intramolecular aromatic addition reactions” describe the synthesis in low yields of benzolactams via cyclization of N-alkoxy-N-acylnitrenium ions.
Kawase, M. et al. in J. Org. Chem., 1989, 54:3394-3403 “Electrophilic aromatic substitution with N-methoxy-N-acylnitrenium ions generated from N-chloro-N-methoxyamides: syntheses of Nitrogen heterocyclic compounds bearing a N-methoxyamide group” describe among others the synthesis of spiro benzodienone lactams by ipso amidation with a nitrenium ion.
These processes present serious inconvenients relating to their yields and to the limited stability of the spiro-fused lactams obtained. Thus, any efficient process for producing functionalised spirolactam compounds in high yield, with various functionalities such as a benzodienone group, and if necessary with stereospecificity, would be a welcome contribution to the art.